The prevalence of anxiety disorders is twice as high in women. The reason for this eleveated prevalence is unclear, partly because most animal research has used only males, and most human research has not considered sex as a variable of interest. This proposal will begin to examine the neurobiological basis for these differences by first studying how natural fluctuations of estrogen in healthy women may influence the resting-state activity and the extinction-induced reactivity of the fear extinction network, including the amygdala, hippocampus, and the ventromedial prefrontal cortex (vmPFC). Additional experiments will involve exogenous manipulations of estrogen in naturally cycling women to see how these manipulations may interact with the functional activation of the fear extinction network. Healthy women will participate in a well-established fear conditioning and extinction protocol at different points of their menstrual cycle. Functional MRI and psychophysiological tools wil be employed to test two overall hypotheses: 1) Naturally elevated estrogen levels during the menstrual cycle will facilitate the resting-state activity and extinction-induced functional reactivity of the fear extinction network, and will be associated with enhanced extinction retention, and 2) Exogenous administration of estrogen to women will enhance extinction retention, which will be associated with enahnced resting-state activity and extinction-induced functional reactivity of this extinction circuitry during extinction recall. Findings from his proposal may help develop sex-specific treatments for anxiety disorders, for example by using hormonal-based pharmacological adjuncts to facilitate the processes of safety learning during therapy. PUBLIC HEALTH RELEVANCE: The incidence of most anxiety and mood disorders is twice as high in women. This proposal will begin to examine the role of endogenous and exogenous estrogen levels on the functional activity and reactivity of the fear extinction network in healthy women. If successful, this approach could lead to developing sex-specific treatments to enhance the outcome of extinction-based therapies using estrogen as an adjunct to such therapies.